Methotrexate for treating rheumatoid arthritis

  • Review
  • Intervention

Authors


Abstract

Background

Methotrexate is a folic acid antagonist widely used for the treatment of neoplastic disorders. Methotrexate inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins by binding to dihydrofolate reductase. Currently, methotrexate is among the most commonly used drugs for the treatment of rheumatoid arthritis (RA). This is an update of the previous Cochrane systematic review published in 1997.

Objectives

To evaluate short term benefits and harms of methotrexate for treating RA compared to placebo.

Search methods

The Cochrane Musculoskeletal Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched from 1966 to 1997 and then updated to November 2013. The search was complemented with a bibliography search of the reference lists of trials retrieved from the electronic search.

Selection criteria

Randomized controlled trials and controlled clinical trials comparing methotrexate (MTX) monotherapy against placebo alone in people with RA. Any trial duration and MTX doses were included.

Data collection and analysis

Two review authors independently determined which studies were eligible for inclusion, extracted data and assessed risk of bias. Outcomes were pooled using mean differences (MDs) for continuous variables or standardized mean differences (SMDs) when different scales were used to measure the same outcome. Pooled risk ratio (RR) was used for dichotomous variables. Fixed-effect models were used throughout, although random-effects models were used for outcomes showing heterogeneity.

Main results

Five trials with 300 patients were included in the original version of the review. An additional two trials with 432 patients were added to the 2013 update of the review for a total of 732 participants. The trials were generally of unclear to low risk of bias with a follow-up duration ranging from 12 to 52 weeks. All trials included patients who have failed prior treatment (for example, gold therapy, D-penicillamine, azathioprine or anti-malarials); mean disease duration that ranged between 1 and 14 years with six trials reporting more than 4 years; and weekly doses that ranged between 5 mg and 25 mg.

Benefits

Statistically significant and clinically important differences were observed for most efficacy outcomes. MTX monotherapy showed a clinically important and statistically significant improvement in the American College of Rheumatology (ACR) 50 response rate when compared with placebo at 52 weeks (RR 3.0, 95% confidence interval (CI) 1.5 to 6.0; number needed to treat (NNT) 7, 95% CI 4 to 22). Fifteen more patients out of 100 had a major improvement in the ACR 50 outcome compared to placebo (absolute treatment benefit (ATB) 15%, 95% CI 8% to 23%).

Statistically significant improvement in physical function (scale of 0 to 3) was also observed in patients receiving MTX alone compared with placebo at 12 to 52 weeks (MD -0.27, 95% CI -0.39 to -0.16; odds ratio (OR) 2.8, 95% CI 0.23 to 32.2; NNT 4, 95% CI 3 to 7). Nine more patients out of 100 improved in physical function compared to placebo (ATB -9%, 95% CI -13% to -5.3%). Similarly, the proportion of patients who improved at least 20% on the Short Form-36 (SF-36) physical component was higher in the MTX-treated group compared with placebo at 52 weeks (RR 1.5, 95% CI 1.0 to 2.1; NNT 9, 95% CI 4 to 539). Twelve more patients out of 100 showed an improvement of at least 20% in the physical component of the quality of life measure compared to placebo (ATB 12%, 95% CI 1% to 24%). No clinically important or statistically significant differences were observed in the SF-36 mental component.

Although no statistically significant differences were observed in radiographic scores (that is, Total Sharp score, erosion score, joint space narrowing), radiographic progression rates (measured by an increase in erosion scores of more than 3 units on a scale ranging from 0 to 448) were statistically significantly lower for patients in the MTX group compared with placebo-treated patients (RR 0.31, 95% CI 0.11 to 0.86; NNT 13, 95% CI 10 to 60). Eight more patients out of 100 showed less damage to joints measured by an increase in erosion scores compared to placebo (ATB -8%, 95% CI -16% to -1%). In the one study measuring remission, no participants in either group met the remission criteria. These are defined by at least five of (≥ 2 months): morning stiffness of < 15 minutes, no fatigue, no joint pain by history, no joint tenderness, no joint swelling, and Westergren erythrocyte sedimentation rate (ESR) of < 20 mm/hr in men and < 30 mm/hr in women.

Harms

Patients in the MTX monotherapy group were twice as likely to discontinue from the study due to adverse events compared to patients in the placebo group, at 12 to 52 weeks (16% versus 8%; RR 2.1, 95% CI 1.3 to 3.3; NNT 13, 95% CI 6 to 44). Compared to placebo, nine more people out of 100 who took MTX withdrew from the studies because of side effects (ATB 9%, 95% CI 3% to 14%). Total adverse event rates at 12 weeks were higher in the MTX monotherapy group compared to the placebo group (45% versus 15%; RR 3.0, 95% CI 1.4 to 6.4; NNT 4, 95% CI 2 to 17). Thirty more people out of 100 who took MTX compared to those who took placebo experienced any type of side effect (common or rare) (ATB 30, 95% CI 13% to 47%). No statistically significant differences were observed in the total number of serious adverse events between the MTX group and the placebo group at 27 to 52 weeks. Three people out of 100 who took MTX alone experienced rare but serious side effects compared to 2 people out of 100 who took a placebo (3% versus 2%, respectively).

Authors' conclusions

Based on mainly moderate to high quality evidence, methotrexate (weekly doses ranging between 5 mg and 25 mg) showed a substantial clinical and statistically significant benefit compared to placebo in the short term treatment (12 to 52 weeks) of people with RA, although its use was associated with a 16% discontinuation rate due to adverse events.

Plain language summary

Methotrexate for treating rheumatoid arthritis

We looked at studies until November 2013 on the effect of receiving methotrexate alone compared to placebo (no treatment) over 12 to 52 weeks in 732 people with rheumatoid arthritis.

Key findings

In the short term treatment of people with rheumatoid arthritis, methotrexate:

- improves pain, function and other symptoms;

- probably reduces joint damage as seen on the x-ray.

Precise information about side effects and complications was not always available. Common side effects may include nausea, vomiting, diarrhoea, loss of appetite, stomach pain, and sores on lips, mouth or throat. Rare complications may include birth defects, kidney, lung and liver problems.

What is rheumatoid arthritis and what is methotrexate?

When you have rheumatoid arthritis, your immune system, which normally fights infection, attacks the lining of your joints making your joints swollen, stiff and painful.
Treatments aim to decrease symptoms and improve your ability to move.

Methotrexate is one of a group of medications called disease-modifying antirheumatic drugs (DMARDs) and it is the most common treatment for rheumatoid arthritis. Methotrexate helps prevent further permanent damage that can happen if rheumatoid arthritis is not treated.

What happens to people with rheumatoid arthritis who take methotrexate alone?

ACR 50 (number of tender or swollen joints and other outcomes such as pain and disability)
- 15 more people out of 100 experienced major improvement in the symptoms of their rheumatoid arthritis after 12 months with methotrexate when compared to placebo (15% absolute improvement).
- 23 people out of 100 who took methotrexate alone experienced major improvement.
- 8 people out of 100 who took a placebo experienced major improvement.

Remission or absence of active disease

In people who took either placebo or methotrexate, none had absence of active disease.

Disability (lower scores mean lower disability)

- People who took methotrexate rated their disability to be 0.27 points lower on a scale of 0 to 3 after 3 to 12 months with methotrexate when compared to placebo (9% absolute improvement).
- People who took methotrexate rated their disability to be between 0.39 and 1.04.
- People who took placebo rated their disability to be between 0.53 and 1.34.

Quality of life - physical component (ability to perform physical activities at least 20% better)

- 12 more people out of 100 perceived their ability to perform physical activities at least 20% better after 12 months with methotrexate alone compared to placebo (12% absolute improvement).
- 39 people out of 100 who took methotrexate alone perceived their ability to perform physical activities at least 20% better.
- 27 people out of 100 who took a placebo perceived their ability to perform physical activities at least 20% better.

Quality of life - mental component

- 5 more people out of 100 perceived their mental well-being better after 12 months with methotrexate alone compared to placebo (5% absolute improvement).
- 26 people out of 100 who took methotrexate alone perceived their mental well-being better.
- 21 people out of 100 who took a placebo perceived their mental well-being better.

X-rays of the joints
- 8 more people out of 100 had less x-ray damage to joints measured by increase in erosion scores of more than 3 units on a scale ranging from 0 to 448 in people who took methotrexate compared to placebo after 12 months (8% absolute reduction).
- 4 people out of 100 who took methotrexate alone had increased damage to joints measured by x-ray.
-12 people out of 100 who took a placebo had increase damage to joints measured by x-ray.

Discontinuations due to adverse events (side effects and complications)
- 9 more people out of 100 discontinued methotrexate due to adverse events after 3 to 12 months compared to placebo (9% absolute withdrawals).
- 16 people out of 100 who took methotrexate alone discontinued methotrexate due to adverse events.
- 8 people out of 100 who took a placebo discontinued placebo due to adverse events.

Serious adverse events
- 1 more person out of 100 experienced serious side effects after 3 to 12 months with methotrexate alone compared to placebo (1% absolute harm).
- 3 people out of 100 who took methotrexate alone experienced serious side effects.
- 2 people out of 100 who took a placebo experienced serious side effects.

Laienverständliche Zusammenfassung

Methotrexat zur Behandlung rheumatoider Arthritis

Wir betrachteten Studien, die bis November 2013 über die Wirkung von Methotrexat allein im Vergleich zu Placebo (keine Behandlung) über 12 bis 52 Wochen bei 732 Menschen mit rheumatoider Arthritis berichteten.

Hauptergebnisse

Die Kurzzeitbehandlung von Menschen mit rheumatoider Arthritis mit Methotrexat bewirkt:

- verminderte Schmerzen, verbesserte Funktion und andere Symptome;

- eine wahrscheinliche Verminderung der Gelenkschäden, die auf der Röntgenaufnahme zu sehen waren.

Genaue Angaben über Nebenwirkungen und Komplikationen waren nicht immer verfügbar. Häufige Nebenwirkungen können Übelkeit, Erbrechen, Durchfall, Appetitlosigkeit, Bauchschmerzen, und Wunden auf den Lippen, im Mund oder Rachen umfassen. Zu den seltenen Komplikationen können Geburtsfehler, Nieren-, Lungen- und Leberprobleme gehören.

Was ist rheumatoide Arthritis und was ist Methotrexat?

Wenn Sie rheumatoide Arthritis haben, greift Ihr Immunsystem, das normalerweise Infektionen bekämpft, die Auskleidung der Gelenke an und lässt Ihre Gelenke anschwellen, sowie steif und schmerzhaft werden.
Behandlungen zielen darauf ab, Symptome zu mindern und Ihre Bewegungsfähigkeit zu verbessern.

Methotrexat ist ein Medikament aus der Gruppe der krankheitsmodifizierenden Antirheumatika (DMARDs), und ist die häufigste Behandlung bei rheumatoider Arthritis. Methotrexate hilft der Entstehung bleibender Schäden vorzubeugen, die entstehen können, wenn rheumatoide Arthritis nicht behandelt wird.

Was passiert mit Menschen mit rheumatoider Arthritis, die ausschließlich Methotrexat nehmen?

ACR 50 (Anzahl der schmerzempfindlichen oder geschwollenen Gelenke und andere Endpunkte wie Schmerzen und Behinderungen)
- 15 von 100 Menschen mehr erfahren eine wesentliche Verbesserung der Symptome ihrer rheumatoiden Arthritis nach 12 Monaten mit Methotrexat im Vergleich zu Placebo (15% absolute Verbesserung).
- 23 von 100 Personen, die ausschließlich Methotrexat nahmen, erlebten eine wesentliche Verbesserung.
- 8 von 100 Personen, die ein Placebo nahmen, erlebten eine wesentliche Verbesserung.

Remission oder Abwesenheit der aktiven Erkrankung

Bei Menschen, die entweder Placebo oder Methotrexat nahmen, erlebte niemand die Abwesenheit der aktiven Erkrankung.

Behinderung (niedrigere Werte bedeuten geringere Behinderung)

- nach 3 bis 12 Monaten bewerteten Menschen, die Methotrexat nahmen, ihre Behinderung auf einer Skala von 0 bis 3 um 0,27 Punkte niedriger, im Vergleich zu Placebo (9% absolute Verbesserung).
- Menschen, die Methotrexat nahmen, bewerteten ihre Behinderung zwischen 0,39 und 1,04.
- Menschen, die Placebo nahmen bewerteten ihre Behinderung zwischen 0,53 und 1,34.

Lebensqualität-physische Komponenten (Fähigkeit, körperliche Aktivitäten um mindestens 20% besser auszuführen)

- nach 12 Monaten bewerteten 12 von 100 Menschen mehr, die Methotrexat nahmen, ihre Fähigkeit, körperliche Aktivitäten um mindestens 20% besser auszuführen, im Vergleich zu Placebo (12% absolute Verbesserung).
- 39 Personen von 100, die ausschließlich Methotrexat nahmen, bewerteten ihre Fähigkeit, körperliche Aktivitäten auszuführen um mindestens 20% besser.
- 27 von 100 Personen, die ein Placebo nahmen, bewerteten ihre Fähigkeit, körperliche Aktivitäten auszuführen um mindestens 20% besser.

Lebensqualität - psychische Komponente

- 5 von 100 Menschen mehr empfanden ein verbessertes psychisches Wohlbefinden nach 12 Monaten mit Methotrexat allein im Vergleich zu Placebo (5% absolute Verbesserung).
- 26 von 100 Personen, die ausschließlich Methotrexat nahmen empfanden ein verbessertes psychisches Wohlbefinden.
- 21 von 100 Personen, die ein Placebo nahmen empfanden ein verbessertes psychisches Wohlbefinden.

Röntgenaufnahmen der Gelenke
- nach 12 Monaten hatten 8 von 100 Menschen mehr, die Methotrexat nahmen weniger Gelenkschäden, gemessen durch eine Zunahme der Erosionspunkte von mehr als 3 Einheiten auf einer Skala von 0 bis 448 (8% absolute Reduktion), verglichen mit Placebo
- 4 von 100 Personen, die ausschließlich Methotrexat einnahmen, hatten mehr Gelenkschäden, die mittels Röntgenstrahlung gemessen wurden.
- 12 von 100 Menschen, die Placebo einnahmen hatten mehr Gelenkschäden, die mit Röntgenstrahlen gemessen wurden.

Therapieabbrüche aufgrund unerwünschter Ereignisse (Nebenwirkungen und Komplikationen)
- 9 von 100 Menschen mehr brachen eine Therapie mit Methotrexat im Vergleich zu Placebo, aufgrund unerwünschter Ereignisse nach 3 bis 12 Monaten ab (9% absolute Therapieabbrüche).
- 16 von 100 Personen, die ausschließlich Methotrexat nahmen, brachen die Therapie mit Methotrexat aufgrund unerwünschter Ereignisse ab.
- 8 von 100 Personen, die ein Placebo nahmen brachen die Therapie aufgrund unerwünschter Ereignisse ab.

Schwere unerwünschte Ereignisse
-1 von 100 Menschen mehr, die ausschließlich Methotrexat nahmen erlebten nach 3 bis 12 Monaten schwerwiegende Nebenwirkungen, verglichen mit Placebo (1% absoluter Schaden).
- 3 von 100 Menschen mehr, die ausschließlich Methotrexate nahmen, erlebten schwerwiegende Nebenwirkungen.
- 2 von 100 Menschen mehr, die ein Placebo nahmen erlebten schwere Nebenwirkungen.

Anmerkungen zur Übersetzung

K. Kunzweiler und I. Töws, Koordination durch Cochrane Schweiz.

Laički sažetak

Metotreksat za liječenje reumatoidnog artritisa

Zaključno sa studenim 2013.g., pregledani su rezultati studija koje su ispitivale učinkovitost monoterapije metotreksatom usporedno s placebom u razdoblju od 12 do 52 tjedna. U studijama je sudjelovalo 732 ljudi oboljelih od reumatoidnog artritisa.

Ključni rezultati

Učinci metotreksata u kratkoročnoj terapiji ljudi oboljelih od reumatoidnog artritisa:

- ublažava bol i druge simptome;

- vjerojatno smanjuje stupanj oštećenja zglobova

Točne informacije o nuspojavama lijeka te komplikacijama nisu uvijek bile dostupne. Česte nuspojave podrazumijevaju mučninu, povraćanje, proljev, gubitak apetita, abdominalne bolove te rane na usmana, ustima i grlu. Rijetke nuspojave uključuju urođene defekte te probleme s bubrezima, plućima i jetrom.

Što je reumatoidni artritis i što je metotreksat?

Kod reumatoidnog artritisa imunološki sustav, koji se uobičajeno bori protiv infekcija, sam napada vlastite ovojnice zglobova što uzrokuje otečenost i ukočenost zglobova te bol.Dostupni tretmani bolesti ublažavaju simptome te poboljšavaju pokretljivost.

Metotreksat je lijek koji pripada skupini antireumatskih lijekova koji utječu na tijek bolesti (disease modifying antirheumatic drugs, DMARD) i najčešći je lijek izbora u terapiji reumatoidnog artritisa. Metotreksat prevenira nastanak daljnjih trajnih oštećenja koja nastaju ako se reumatoidni artritis ne liječi.

Kako reagiraju pacijenti na monoterapiji metotreksatom?

ACR 50 (kriterih prema broju osjetljivih ili otečenih zglobova, bolovima ili invalidnosti) -15 od 100 ljudi osjetilo je velika poboljšanja simptoma reumatoidnog artritisa nakon 12 mjeseci liječenja metotreksatom u usporedbi s placebo kontrolom (apsolutno poboljšanje od 15%)- 23 od 100 ljudi tretiranih metotreksatom osjetilo je veliko poboljšanje - 8 od 100 ljudi u placebo grupi doživjelo je veliko poboljšanje simptoma

Remisija ili odsutnost aktivne faze bolesti

U skupinama koje su uzimale metotreksat i placebo nitko od ispitanika nije bio u fazi remisije.

Invalidnost (niži rezultati kriterija označavaju niži stupanj invalidnosti)

Tri do dvanaest mjeseci od početka liječenja, oboljeli koji su uzimali metotreksat ocijenili su svoj stupanj onesposobljenosti nižim za 0,27 boda na ljestvici od 0 do 3 u usporedbi s placebom (apsolutno poboljšanje od 9%).Osobe koje su uzimale metotreksat ocijenile su stupanj svoje onesposobljenosti između 0,39 i 1,04. Usporedno, osobe koje su uzimale placebo ocijenile su svoj stupanj onesposobljenosti između 0,53 i 1,34.

Kvaliteta života - fizički aspekt (sposobnost izvođenja fizičkih aktivnosti bolja za najmanje 20%)

Nakon 12 mjeseci terapije metotreksatom, 12 od 100 ljudi ocijenilo je svoju sposobnost izvođenja fizičkih aktivnosti boljom za najmanje 20% u usporedbi s placebom (apsolutno poboljšanje od 12%39 od 100 ljudi koji su uzimali samo metotreksat ocijenilo je svoju sposobnost izvođenja fizičkih aktivnosti boljom za bar 20%.
27 od 100 ljudi koji su uzimali placebo ocijenilo je svoju sposobnost izvođenja fizičkih aktivnosti boljom za najmanje 20%.

Kvaliteta života - psihički aspekt

Nakon 12 mjeseci terapije, 5 od 100 ljudi osjetilo je poboljšanje psihičkog zdravlja nakon terapije samim metotreksatom u usporedbi s placebom (apsolutno poboljšanje od 5%).Dodatnih 26 ljudi od 100 osjetilo je poboljšanje psihičkog zdravlja nakon terapije metotreksatom.Usporedno, 21 od 100 ljudi koji su uzimali placebo također su osjetili poboljšanje svog psihičkog zdravlja nakon terapije.

Snimke zglobova Nakon 12 mjeseci terapije metotreksatom, 8 ljudi od 100 imalo je manja oštećenja zglobova mjerena porastom rezultata erozije za više od 3 jedinice na ljestvici od 0 do 448 (apsolutno poboljšanje od 8%). Kod 4 ljudi od 100 otkriveno je veće oštećenje zglobova.Kod 12 od 100 osoba koje su uzimale placebo otkriven je porast oštećenja zglobova.

Prekidanje terapije zbog neželjenih reakcija (nuspojave i komplikacije) Nakon 3 do 12 mjeseci terapije, 9 od 100 ljudi odustalo je od terapije metotreksatom zbog nuspojava (9%-tno apsolutno )16 osoba od 100 koje su uzimale metotreksat odustalo je od terapije zbog nuspojava.Od 100 ljudi na terapiji placebom, 8 je odustalo zbog nuspojava.

Ozbiljne nuspojave.
Nakon 3 do 12 mjeseci terapije metotreksatom u usporedbi s placebom, jedna osoba dodatno je odustala zbog ozbiljnih nuspojava (apsolutna štetnost od 1%).
Ukupno 3 od 100 ljudi prekinulo je terapiju metotreksatom zbog pojave ozbiljnih nuspojava.
Usporedno, od 100 ljudi koji su uzimali placebo, 2 osobe prekinule su terapiju zbog ozbiljnih nuspojava.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Petra Gilja
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

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